Effects of a Novel Class III Antiarrhythmic Agent, NIP-142, on Canine Atrial Fibrillation and Flutter

Abstract

The effects of a new benzopyran derivative, NIP-142, on atrial fibrillation (AF) and flutter (AFL) and on electrophysiological variables were studied in the dog. NIP-142 (3mg/kg) was administered intravenously to pentobarbital-anesthetized beagles during vagally-induced AF and during AFL induced after placement of an intercaval crush. Isolated canine atrial tissues were studied using standard microelectrode technique. NIP-142 terminated AF in 5 of 6 dogs after an increase in fibrillation cycle length (CL) and prevented reinitiation of AF in all 6 dogs. NIP-142 terminated AFL in all 6 dogs without any appreciable change in flutter CL, and prevented reinitiation of AFL in all 6 dogs. NIP-142 prolonged atrial effective refractory periods (11+/-5%, 3+/-3%, 12+/-3%, and 10+/-5% from the baseline value at basic CLs of 150, 200, 300, and 350ms, respectively) without changes in intraatrial conduction time. The prolongation of the atrial effective refractory period was greater in the presence of vagal stimulation. NIP-142 decreased action potential phase-1 notch and increased phase-2 plateau height without making any changes in the action potential duration, although it did reverse carbachol-induced shortening of the action potential duration. In conclusion, NIP-142 is effective in treating AFL and vagally-induced AF by prolonging atrial refractoriness.

“Early” Class III Drugs for the Treatment of Atrial Fibrillation

“…6 Several experimental I Kur blockers are under investigation. 7,8 One of them (AVE0118), which, in addition to I Kur , blocks the I to current, is evaluated in the present study. We hypothesized that in electrically remodeled atria, blockade of the early repolarizing currents restores the plateau of the action potential, thereby exerting an antifibrillatory effect.…”

Acetylcholine-Activated Potassium Channel as a Novel Target for AF Treatment

“…The ERP prolongation by NIP-142 was greater in the presence of VNS than normal condition (Nagasawa et al, 1999). We also reported that this compound at 3 mg/kg prolonged atrial ERP by about 20 ms under VNS, but at doses up to 10 mg/kg it had no significant atrial ERP prolongation effect without VNS .…”

“…Injection of NIP-142 (3 mg/kg) terminated AF after increase in fibrillation cycle length and prevented reinitiation of AF in VNS-induced model. This compound terminated macroreentry type of atrial flutter induced after placement of an intercaval crush without affecting atrial flutter cycle length (Nagasawa et al, 1999). NIP-142 prolonged atrial ERP by about 10% without affecting intraatrial and interatrial conduction times in these models, which suggested that the antiarrhythmic effects were achieved by the atrial ERP prolongation.…”

“…NIP-142-induced prolongation of atrial ERP was greater than that of ventricular ERP in AF models (Nagasawa et al, 1999). Because ventricular ERP or QT prolongation is not suitable for drug-induced TdP (Thomsen et al, 2003(Thomsen et al, , 2004, we also evaluated the proarrhythmic risk of NIP-142 using the methoxamine-sensitized rabbit model, known as Carlsson model (Carlsson et al, 1990).…”

Blockade by NIP-142, an Antiarrhythmic Agent, of Carbachol-Induced Atrial Action Potential Shortening and GIRK1/4 Channel

“…This compound terminated the canine vagal stimulation-induced atrial fibrillation and canine Y-shaped incision-induced atrial flutter (7). These effects have been attributed to prolongation of atrial refractory period.…”